Narrative

Our SPORE provides a wide spectrum of capabilities enabling a broad translational research program aimed at reducing the disease burden of gastrointestinal cancers though improved risk assessment, early detection and therapeutic interventions.

This application for continuation of the Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins supports a highly interactive, multidisciplinary program. Four research projects, four cores, a career development and a research developmental program are proposed to extend our translational research in colorectal and pancreatic cancer.

Administrative Core

Core Summary/Abstract

The primary function of the Administrative Core is to provide for the overall organizational, administrative and scientific management of the GI SPORE Program.

This will be accomplished by the following aims:

Provide the organizational structure to efficiently enable all SPORE activities.

Provide the administrative foundation for the management of SPORE activities, including research projects, shared resources Cores, developmental research projects, career enhancement programs and supplemental actives.

Provide overall scientific management for the GI SPORE program.

This Core will be responsible for managing the SPORE and disseminating information within the SPORE. The Core will also manage external interactions.

Project 1, Improving Pancreatic Cancer Risk Assessment

Project 1 Summary/Abstract

Our overall foundation is that there are identifiable genetic predispositions to the development of pancreatic cancer. Our prior work has established the importance of inherited factors in the development of pancreatic cancer, and identified BRCA2, PALB2 and ATM as familial pancreatic cancer genes. However, the familial clustering is still unexplained for 80% of pancreatic cancer families. This leads to our overall translational goals; to increase our scientific evidence base to inform genetic counseling and risk assessment of at-risk individuals by identifying new pancreatic cancer genes and to identify people at high-risk who would benefit most from future chemoprevention trials and efforts to screen for early, and therefore potentially curable, pancreatic neoplasia. As part of this project we will 1) To determine the contribution of germline structural variants to pancreatic cancer susceptibility: 2) To evaluate and characterize candidate pancreatic cancer susceptibility genes; 3) To determine if personal or family histories of cancers other than pancreatic cancer can be used to better estimate the risk of developing pancreatic cancer 3B) to develop and validate an enhanced and clinically practical pancreatic cancer risk stratification.

Project 2 Summary/Abstract

Immune checkpoint inhibitors (ICIs) are providing durable clinical responses in about 20% of cancer patients. But these agents have minimal effect in cancers without intratumoral T cells. Approaches that turn currently unresponsive cancers into ones that are more “antigenic” are needed to sensitize tumors to ICIs. Tumor genome mutations can express mutant proteins that are tumor specific and not expressed on normal cells (neoantigens), and cancers with the highest mutational burdens are more likely to respond to single agent ICIs. However, most cancers have lower mutational loads resulting in lower antigenicity, weaker endogenous T cell repertoires, and T cells in the tumor.

Emerging data suggest that it should be possible to develop approaches that combine a neo-antigen targeting vaccine to activate and expand the limited repertoire of T cells specific for the expressed neo-antigens found in low mutation cancers, with ICIs to induce clinically relevant anti-tumor responses. But challenges to successful immunization include knowledge about the repertoire and functional state of pre-existing anti-tumor T cells, identification of the best adjuvants, and approaches that more precisely predict which expressed neo-antigens are the best T cell targets for immunization.

We hypothesize that neoantigens are attractive vaccine targets that can raise T cells to be available for further activation by ICIs. Aim 1: we will determine baseline prevelance of pre-existing neoepitope recognizing T cells using a novel T cell functional assay we developed - Mutation Associated Neoantigen Functional Expansion of Specific T cells (MANAFEST). Aim 2: we will evaluate neoantigen targeted combination immunotherapy in PDA patients. Aim 3: we will evaluate neo-antigen targeted combination immunotherapy in MSS CRC patients.

Project 3, Diagnosis and Management of Pancreatic Cysts

Project 3 Summary/Abstract

Pancreatic cysts are common and certain types can be precursors to invasive pancreatic cancer. Because of the risk of complications and death associated with either the under or over treatment of pancreatic cysts, better diagnostic methods for distinguishing pancreatic cyst type are required. The goal of this translational project is to develop a test that integrates clinical, imaging, molecular and protein data, to improve the management of pancreatic cysts, which will ultimately be used in clinical practice.

Over one million individuals are identified with pancreatic cysts every year. IPMNs and MCNs, are pre-cursors to pancreatic cancer, and offer the opportunity for the early detection, or even prevention, of pancreatic cancer. In contrast, serous cystadenomas or pseudocysts, are benign. Currently tools are inadequate to fully delineate these lesions prior to surgical resection, with up to 68% of the operations performed on patients with a pancreatic cyst ultimately found to be unnecessary. Guidelines recommend lifelong surveillance for IPMNs, however this is based on the lowest level of scientific evidence. Furthermore, no data exists on the molecular progression of IPMNs and MCNs in situ. We developed a Comprehensive Cyst (CompCyst) EUS companion test which combines clinical, radiological, genetic and protein marker data. In an initial evaluation of 862 surgically resected pancreatic cysts, the CompCyst test had a superior performance for identifying cysts which required surgery, needed surveillance, or were benign, compared with the current routine evaluation. The Aims of the proposed project are to: Aim 1: Evaluate the genetic and clinical natural history of pancreatic cysts in a prospective international study. Aim 2: Evaluation and optimization of approaches for the management of pancreatic cysts. Aim 3: Develop a Second-Generation CompCyst test (CompCyst2). The overarching goal of Project 3 is to develop a clinically relevant tool which will beincorporated into clinical practice and will improve outcomes for patients with pancreatic cysts, specifically avoiding unnecessary surveillance or surgical resection.

Project 4 Summary/Abstract

Immunotherapy has become a game changer for about 20% of patients with metastatic cancers who, until now, would die quickly of their disease. This new class of immunotherapies induce durable responses that can last for years without further therapy. These agents (immune checkpoint inhibitors) act on T cells that are inactivated due to immune checkpoint signals that inhibit their infiltration into and function within tumors. But for about 80% of patients, immunotherapy has not been effective, and immune unresponsiveness is likely the result of failure to activate effector T cells together with the existence of multiple suppressive signals rather than a predominant immune checkpoint signal within resistant tumors. Accumulating data suggests that it is possible to convert non-immunogenic tumors into one that respond to immunotherapy. Thus, this proposal will address the next big question in cancer immunotherapy: why do some cancers respond to checkpoint immunotherapy and exhibit durable responses, while others either develop resistance (adaptive resistance) or are naturally resistant. Understanding primary and adaptive resistance mechanisms will translate into effective scientifically driven combination immunotherapies that combat resistance.

Our group has led the development of both single agent and combination therapy for pancreatic adenocarcionoma (PDA) and colorectal carcinoma (CRC) and have recently received FDA approval for Pembrolizumab for the treatment of patients with microsatellite instability (MSI) high tumors. In addition, we have shown that treatment of patients with a vaccine can induce cancer specific T cells that infiltrate into PDA and CRC tumors, opening the door for novel combination immunotherapies. In this proposal, we will use specimens already collected and prospectively being collected on trials that are demonstrating both sensitivity and primary and adaptive resistance to s, to define additional signals required to convert insensitive tumors into ones that respond to immunotherapy.

Core 1, Statistics/Bioinformatics

Core Leaders: Drs. Elizabeth Sugar and Robert Scharpf

Core Summary/Abstract

The goal of the Gastrointestinal Biostatistics and Bioinformatics Core (GI-BBC) is to provide wide-ranging, high-quality statistical and bioinformatics support to the GI SPORE. The primary aim of the GI-BBC is to assist GI SPORE investigators in the design, conduct and analysis of laboratory and clinical studies proposed in this SPORE application. The GI-BBC will focus its efforts on assisting both the clinical and laboratory investigators in translating their pre-clinic studies into clinical studies by providing state-of-the-art experimental designs and analyses through statistical consultation and in collaboration with respect to methodology, feasibility, analysis, and reporting of clinical and laboratory studies. In addition, the GI-BBC will serve as an ongoing resource for all GI-SPORE investigators.

Core 2, Tissue Research and Logistics

Core Leaders: Dr. Robert Anders

Core Summary/Abstract

The purpose of this shared resource is to provide human tissues, biological fluids, and expert pathologic interpretation for investigators in all of the projects under the direction of expert pathologists. The Histopathology and Tissue/Biologic Fluids Resource has been in existence since 1986 and expanded under the support of the GI SPORE. As of this year, the Resource includes 3156 banked colorectal carcinoma resection specimens, 363 colorectal adenoma samples, 430 hepatic metastases of colorectal carcinoma, 1204 pancreatic carcinoma specimens, 843 xenografts of colorectal carcinoma, 101 pancreatic carcinoma xenografts, 6085 blood specimens from individuals at risk for colorectal carcinoma, and 2122 blood specimens from patients with pancreatic carcinoma. Formalin-fixed paraffin-embedded tissues, frozen materials and clinical and outcome data are available for the vast majority of resection specimens. This resource has collections to include high quality snap frozen and formalin fixed samples of end stage pancreatic or colorectal cancer from 125 rapid autopsy participants.

Core 3, Familial and Population Cancer Registries

Core Co-Directors: Drs. Frank Giardiello and Alison Klein

Core Summary/Abstract

The genesis of colorectal and pancreatic cancer involves the interaction of environmental and heritable causes. Key to discoveries in diagnosis and treatment of these malignancies is the understanding of these factors by investigation of well-characterized and available patient data and specimens.

The goal of Core 3 is to provide SPORE and other investigators with these materials to support the research of familial, environmental and molecular genetic factors in both colorectal and pancreatic cancer. With this regard, a registry and clinical study of patients with hereditary colorectal cancer and polyposis syndromes were founded at the Johns Hopkins Hospital in 1973. In 1982, the Bowel Tumor Working Group was formed to study the pathobiology and molecular genetics of colorectal tumors. In 1991, the Core 3 was formed.

The specific aims of our Family and Population Core are:

To collect family history, medical history, pathological records, environmental/exposure and dietary data from at risk and affected individuals with colorectal and pancreatic neoplasms and associated syndromes.

To procure specimens including blood, stool, saliva and cyst fluid in at-risk and affected individuals with colorectal and pancreatic neoplasms and associated syndromes.

Career Enhancement Program

Program Director: Dr. Scott Kern

Program Summary/Abstract

The goal of this proposed program is to provide funds for career development of faculty members who are or will be specifically involved in translational research in gastrointestinal cancer. Eligible candidates include faculty members at any level in the University who wish to direct their efforts into translational research in gastrointestinal cancer. One Career Enhancement awardee will be selected each year. We anticipate providing multiple years of support to each awardee. Support for the “out years”, those beyond the maximum supported time permitted by SPORE guidelines, is provided by institutional funds dedicated to the GI SPORE.

Developmental Research Program

Program Director: Dr. Bert Vogelstein

Program Summary/Abstract

The Developmental Research Program of our GI SPORE is designed to provide initiating funds for novel explorations related to GI cancer and integrate the awardee into the SPORE community. The Program continues to be a major focus of the SPORE because it provides for a continuous flow of innovative ideas and activity to stimulate investigation in the context of SPORE translational research. The Developmental Research Program provides a means to respond to new opportunities, and is designed to encourage and facilitate new research efforts. The Program takes advantage of the broad expertise of researchers at The Johns Hopkins University and of external investigators by providing funds for pilot projects with potential for development into full-fledged translational research avenues, collaborations, and new methodologies integration into other Research Projects.